Genetics of progressive multifocal leukoencephalopathy: update on case reports with an inborn error of immunity and risk variants found in drug-linked cases

Abstract

A genetic predisposition to PML is now substantially supported by case reports of patients molecularly diagnosed with an inborn error of immunity (IEI) and progressive multifocal leukoencephalopathy (PML). Over the past 10 years, 4 IEI genes linked to PML has now grown to 26 as of 2025. Of these 26 genes believed to be causal of an IEI and PML, 24 (92%) are also linked with hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)-a severe hyper-inflammation syndrome associated with several IEI genes, most notably in 4 genes (PRF1, STX11, STXBP2, UNC13D) causing familial forms of the syndrome. Many HLH-linked genes are associated with life-threatening Epstein-Barr virus infections, which analogously suggests JC virus infection plus presence of a pathogenic variant in an HLH-linked IEI gene also increases risk of PML. PML also occurs as a serious adverse event for a subset of immunosuppressive therapies (e.g., natalizumab and rituximab) used to treat patients with immune disorders (e.g., multiple sclerosis and hematological malignancies). Recently, 4 PML risk variants were reported for use in a PML risk test to screen patients who are considering treatment with PML-linked therapies. Interestingly, of the 4 genes with a PML risk variant, 2 (LY9 and STXBP2) cause or are linked to HLH. The aim of our review is two-fold: (1) raise awareness among researchers and clinicians (e.g., neurologists, oncologists, and rheumatologists) that patient genetics are a key risk factor for PML, and (2) further reinforce the rationale for screening at-risk patients for PML risk variants before prescribing a PML-linked drug.

Keywords: JC virus; PML; hemophagocytic lymphohistiocytosis; immunodeficiency; inborn error of immunity; natalizumab; progressive multifocal leukoencephalopathy; rituximab.

Figure 1

Genes reported for previously published PML cases with an IEI diagnosis, HLH diagnosis, or positive for a PML genetic risk variant (see Supplementary Table 1) (10, 20, 35–38, 96–127). (A) Each patient was genetically diagnosed with an IEI plus developed PML or diagnosed with HLH (indicated) and PML. All other PML cases were not reported to also have HLH, but 19 of 26 IEI genes are linked to an increased risk of EBV and/or HLH as associated features (7, 13, 16–28, 30–34, 128). (B) Each patient tested positive for a PML risk variant (5, 6). Two genes (C8B and FCN2) are in the complement pathway (129–133) and two genes (LY9 and STXBP2) are linked to EBV/HLH (see Figure 2).

Figure 2

Protein network analysis of PML-linked IEI genes using STRING (55). Default STRING settings were used for 37 genes: 26 IEI + PML case report genes (see Figure 1), 9 SLAMF gene family members (41, 42), SLAMF-interacting gene SH2D1A (an IEI gene that causes XLP1) (7), and 2 PML risk genes (SLAMF gene LY9 and IEI gene STXBP2) (5, 6). The protein–protein interaction (PPI) enrichment p-value is < 1.0E-16. ZBTB24 is the only unconnected IEI & PML gene (upper right), see text. SLAMF gene CD48 (SLAMF2) was recently identified as HLH-linked and a potential new IEI, the first member of this gene family found to cause an immune disorder (45, 134). Both IEI and SLAMF genes have been linked to increased risk of autoimmune diseases (48) and hematological cancers (135, 136).